title: Syk regulates multiple signaling pathways leading to CX3CL1 chemotaxis in macrophages.
abstract: Several studies have clearly established the importance of the interaction between macrophages and CX3CL1 in the progression of disease. A previous study demonstrated that Syk was required for CX3CL1-mediated actin polymerization and chemotaxis. Here, we delineated the signaling cascade of Syk-mediated cell migration in response to CX3CL1. Inhibition of Syk in bone marrow-derived macrophages or reduction of Syk expression using siRNA in RAW/LR5 cells indicated that Syk was required for the activation of PI3K, Cdc42, and Rac1. Also, reduction in WASP or WAVE2 levels, common downstream effectors of Cdc42 or Rac1, resulted in impaired cell migration to CX3CL1. Syk indirectly regulated WASP tyrosine phosphorylation through Cdc42 activation. Altogether, our data identify that Syk mediated chemotaxis toward CX3CL1 by regulating both Rac1/WAVE2 and Cdc42/WASP pathways, whereas Src family kinases were required for proper WASP tyrosine phosphorylation.
authors.affiliation: Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Yeshiva University, Bronx, New York 10461, USA. hapark@aecom.yu.edu
authors.forename: Haein
authors.initials: H
authors.lastname: Park
authors.forename: Dianne
authors.initials: D
authors.lastname: Cox
mesh_terms: D000818:Animals; D002460:Cell Line; D054428:Chemokine CX3CL1 / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D009479:Neuropeptides / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D000072377:Syk Kinase; D051316:Wiskott-Aldrich Syndrome Protein / Q000378:metabolism; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein
chemical_list: D054428:Chemokine CX3CL1; C515539:Cx3cl1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; C484602:Rac1 protein, mouse; C492303:Wasf2 protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein; D051300:Wiskott-Aldrich Syndrome Protein Family; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein